The treatment of infectious diseases is a major clinical concern worldwide. As infectious agents become resistant to more and more antibiotic compounds, the development of new and more efficient infectious agents is a major task in the art. Resistance to chemotherapy is a common clinical problem in patients with infectious diseases. During the treatment of infections, the drug targets of prokaryotic or eukaryotic microorganism cells are often found to be refractory to a variety of drugs that have different structures and functions. This phenomenon has been referred to as multidrug resistance (MDR).
The incidence of the multiple antimicrobial resistance of bacteria which cause infections in hospitals/intensive care units is increasing, and finding microorganisms insensitive to more than 10 different antibiotics is not unusual. Examples of such resistant bacteria include methicillin-resistant and methicillin-vancomycin-resistant Staphylococcus aureus; vancomycin-resistant enterococci, such as Enterococcus faecalis and Enterococcus faecium; penicillin-resistant Streptococcus pneumoniae, and cephalosporin and quinolone resistant gram-negative rods (coliforms), such as E. coli, Salmonella species, Klebsiella pneumoniae, Pseudomonas species and Enterobacter species. More recently, pan antibiotic resistant gram-negative and gram-positive bacilli have emerged.
The rapidity of emergence of these multiple antibiotic-resistant bacteria is not being reflected by the same rate of development of new antibiotics, and it is therefore conceivable that patients with serious infections soon will no longer be treatable with the currently available anti-infective agents. Several international reports have highlighted the potential problems associated with the emergence of antimicrobial resistance in many areas of medicine and also outlined the difficulties in the management of patients with infections caused by these microorganisms.
Although most of the hardier microorganisms are present in hospitals, strains of multidrug resistant bacteria, such as Streptococcus pneumoniae and Mycobacterium tuberculosis have also caused serious community-acquired infections. The prevalence of drug-resistant Streptococcus pneumoniae has increased 60-fold since 1980 with 51% and 8% of isolates demonstrating intermediate- or high-level resistance to penicillin or third-generation cephalosporins, respectively. Thus, pneumococcal pneumonia is becoming more difficult to treat with first-line anti-infective agents. Resistant bacteria from hospitals can be introduced into the community via patients discharged for continued treatment at home taking with them, for example, multidrug resistant Staphylococcus aureus and vancomycin resistant enterococci.
Phenothiazines and thioxanthenes are used clinically as neuroleptic and antiemetic agents. Phenothiazines, and structurally related antipsychotic agents, inhibit several cellular enzymes and block the function of critical cellular receptors. The extrapyramidal side effects associated with antipsychotic therapy are attributed to dopamine receptor binding. In general, these extrapyramidal side effects have proven to be dose limiting in clinical trials using phenothiazines and thioxanthenes in non-psychotic areas, such as anti-cancer treatment. The relevant serum levels of phenothiazines and thioxanthenes are generally in the range from approximately 0.3 μg/l to 0.5 mg/l (0.3 ng/ml to 0.5 μg/ml) in order to avoid potential side effects.
Phenothiazines and thioxanthenes have been shown in themselves to have modest, but broad, antimicrobial activities. MICs (the minimal concentration of compound at which the infectious agent is inhibited) are generally high above clinically relevant concentrations inasmuch as the disclosed minimum effective concentrations in vitro are in the order from approximately 20 mg/l to several hundreds mg/l. Although the mechanism by which phenothiazines modulate MDR is not yet clear, it has been suggested that their pharmacological properties may be mediated at least in part by the inhibition of efflux pumps. Also, promethazine has been recognised as an effective antiplasmid agent in cultures containing bacterial species such as Escherichia coli, Yersinia enterocolitica, Staphylococcus aureus and Agrobacterium tumefaciens. The concentrations used, however, are generally high above clinically relevant concentrations.
It has recently been shown that certain phenothiazine and thioxanthene derivatives used as anti-infective compounds are surprisingly effective in assisting in killing infectious agents, such as multidrug resistant infectious agents, even at clinically relevant concentrations, when used in combination with an anti-infective agent.
Accordingly, WO2005/105145 A discloses the use of certain thioxanthene derivatives and phenothiazine derivatives as chemosensitising compounds. Chemosensitising compounds are anti-infectious compounds for the treatment of infectious disease in combination with an anti-infectious agent. The disclosed derivatives all have a nitrogen containing substituent on the thioxanthene or phenothiazine backbone. The problem solved according to that disclosure relates to a combination treatment of infective diseases and does not teach that the disclosed compounds are suited for administration as single anti-bacterial agents but rather that the disclosed compounds are suited for a combination treatment where another antibiotic agent is used simultaneously in combination with the disclosed compounds. The compounds according to the present invention differ from the compounds according to WO2005/105145 A e.g. in the substitution of C for N in the atom linking substituents R9 and R10 according to the present invention.
WO2008/080408 A discloses the surprising finding that a sub-group of the compounds disclosed in WO2005/105145 A may in fact be useful as sole antibacterial agents. This finding is surprising as it was thought that the function of the compounds according to WO2005/105145 A as chemosensitising compounds was to reverse resistance against one or more anti-infectious agent.
EP-A-0338532 discloses the use of clopenthixol among other compounds as an anti-protozoal agent.
Kolaczkowski M et al., International Journal of Antimicrobial Agents (2003) Vol. 2, No. 3 discloses trans-flupenthixol among a range of compounds as modulators of yeast multidrug resistance.
Kristensen et al., International Journal of Antimicrobial Agents (2000) Vol. 14, No. 3 discloses cis- and trans-flupenthixol as HIV-inhibitors.
It is clear that the increase in resistance to anti-infective agents, such as antibiotics, present a major impediment to the treatment of infections. Thus, there is an urgent need for new anti-infective agents. There is also a need for compounds inhibiting and reversing drug resistance and development of drug resistance in infective agents.
The object of the present invention is to provide anti-infective agents capable of killing or inhibiting growth of clinically relevant microorganisms, especially resistant, including multidrug resistant, cells or microorganisms by the administration of clinically relevant amounts of such anti-infective agents to a subject in need thereof.
Further, an object of the present invention was to provide chemosentisising agents capable of, in combination with an additional anti-infective agent, killing or inhibiting growth of clinically relevant microorganisms, especially resistant, including multidrug resistant, cells or microorganisms by the administration of clinically relevant amounts of such anti-infective agents to a subject in need thereof.